HK40000354A - Polymorphs of compound as well as preparation method and use thereof - Google Patents

Description

Polymorphic forms of a compound, processes for their preparation and their use

The present application claims priority of a prior application entitled "polymorphic form of a compound, process for its preparation and use" filed in 2017, 4, month 28, to the chinese intellectual property office under patent application No. 201710295287.9. The entire content of this prior application is incorporated by reference into this application.

Technical Field

The invention belongs to the field of pharmaceutical crystal forms, and particularly relates to a polymorphic form of a compound, a preparation method and application thereof, in particular to the polymorphic form of (3R,6S) -6-sulfamoylamino-1- (thiazole-2-yl) -3- (2,3, 4-trifluorophenyl) -3,5,6, 7-tetrahydropyrrolo [1,2-c ] pyrimidine-4-methyl formate, and the preparation method and application of the polymorphic form.

Background

Hepatitis b virus belongs to the hepadnaviridae family. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis b virus also causes many other clinical manifestations in the pathological morphology, in particular chronic inflammation of the liver, cirrhosis and canceration of the hepatocytes. In addition, co-infection with hepatitis delta can have adverse effects on the progression of the disease.

Conventional agents approved for the treatment of chronic hepatitis are interferon and lamivudine (iamvudine). However, interferons have only moderate activity and high toxic side effects; while lamivudine has good activity, its drug resistance increases rapidly during treatment and often has a rebound effect after cessation of treatment, the IC of lamivudine (3-TC)₅₀The value was 300nM (Science,299(2003), 893-896).

Deres et al reported heteroaromatic substituted dihydropyrimidine (HAP) compounds represented by Bay41-4109, Bay39-5493, which are capable of inhibiting HBV replication by preventing normal nucleocapsid formation. Bay41-4109 showed good drug metabolism parameters in clinical studies (Science,299(2003), 893-896). Studies on the mechanism of action have found that heteroaryl ring substituted dihydropyrimidines alter the angle between nucleocapsid forming dimers by interacting with the 113-143 amino acid residues of the core protein, resulting in the formation of unstable swollen nucleocapsids, accelerating the degradation of the core protein (biochem. pharmacol.,66(2003), 2273-2279). In addition, patent application WO2015180631 also discloses compounds as HBV inhibitors, and at present, there is still a need to develop new compounds which can be effectively used as antiviral drugs, especially as drugs for treating and/or preventing hepatitis b, and especially, drug crystal forms which are improved in stability, hygroscopicity, drug efficacy and the like and more suitable for drug preparation, so as to obtain good effects in the pharmaceutical and administration phases.

Disclosure of Invention

To solve the problems of the prior art, the present invention provides a polymorph of methyl (3R,6S) -6-sulfamoylamino-1- (thiazol-2-yl) -3- (2,3, 4-trifluorophenyl) -3,5,6, 7-tetrahydropyrrolo [1,2-c ] pyrimidine-4-carboxylate represented by the following formula compound 1:

the invention provides a crystal form II of a compound 1 hemihydrate, which has characteristic peaks at 4.15 +/-0.20 °, 4.99 +/-0.20 °, 8.78 +/-0.20 °, 9.44 +/-0.20 °, 18.47 +/-0.20 ° and 18.93 +/-0.20 ° in X-ray powder diffraction expressed by a 2 theta angle by using Cu-Kalpha radiation.

preferably, the crystal form II has characteristic peaks at 4.15 +/-0.20 degrees, 4.99 +/-0.20 degrees, 7.33 +/-0.20 degrees, 8.78 +/-0.20 degrees, 9.44 +/-0.20 degrees, 10.00 +/-0.20 degrees, 18.47 +/-0.20 degrees and 18.93 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-K α radiation.

preferably, the crystal form II has the characteristic that the X-ray powder diffraction has the peak values of +/-0.20 DEG, 4.99 +/-0.20 DEG, 7.33 +/-0.20 DEG, 7.88 +/-0.20 DEG, 8.78 +/-0.20 DEG, 9.44 +/-0.20 DEG, 10.01 +/-0.20 DEG, 10.96 +/-0.20 DEG, 11.61 +/-0.20 DEG, 12.54 +/-0.20 DEG, 14.18 +/-0.20 DEG, 16.65 +/-0.20 DEG, 17.49 +/-0.20 DEG, 18.47 +/-0.20 DEG, 18.93 +/-0.20 DEG, 19.62 +/-0.20 DEG, 20.13 +/-0.20 DEG, 21.49 +/-0.20 DEG, 22.08 +/-0.20 DEG, 22.51 +/-0.20 DEG, 23.59 +/-0.20 DEG, 24.68.20 DEG, 25.37 +/-0.20 DEG, 26.56 +/-0.56 +/-0.24.20 DEG, 27.20 +/-0.20 DEG, 27.20 DEG, 20 DEG.

preferably, the compound 1 in the form II is obtained by using Cu-K α radiation, and X-ray powder diffraction peaks expressed by 2 θ angle are shown in table 1, with a tolerance range ± 0.20 °:

table 1 XRPD analysis data for compound 1 form II

Preferably, the crystalline form II of the compound has a powder X-ray diffraction pattern substantially as shown in figure 1.

According to the invention, the Differential Scanning Calorimetry (DSC) analysis of said crystalline form II shows a first endothermic peak at a heating to peak temperature of about 103 ℃, an exothermic peak at a heating to peak temperature of about 149 ℃, and a second exothermic peak at a heating to peak temperature of about 176 ℃.

According to the present invention, the thermogravimetric analysis (TGA) of said crystalline form II is having a weight loss of about 1.8% upon heating to 120 ℃.

Preferably, the crystalline form II has a DSC-TGA profile substantially as shown in figure 2.

Preferably, the crystalline form II has a scanning electron micrograph substantially as shown in figure 3.

According to the invention, the purity of said form II may be 95% or more, preferably 99% or more, for example 99.3% or 99.6%.

the invention also provides a compound 1 monohydrate in a crystal form IV, which has characteristic peaks at 5.04 +/-0.20 degrees, 7.20 +/-0.20 degrees, 7.68 +/-0.20 degrees, 9.81 +/-0.20 degrees, 10.08 +/-0.20 degrees and 14.43 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.

preferably, the crystal form IV has characteristic peaks at 5.04 +/-0.20 degrees, 7.20 +/-0.20 degrees, 7.68 +/-0.20 degrees, 9.35 +/-0.20 degrees, 9.81 +/-0.20 degrees, 10.08 +/-0.20 degrees, 14.43 +/-0.20 degrees and 18.07 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.

preferably, the crystal form IV uses Cu-K α radiation, and the X-ray powder diffraction represented by the angle 2 theta has the characteristic that the peak of the.

preferably, said form IV of compound 1 is obtained by using Cu-K α radiation, and X-ray powder diffraction peaks expressed in 2 θ angle are shown in table 2, with a tolerance range ± 0.20 °:

table 2 XRPD analysis data for compound 1 form IV

Preferably, the form IV has a powder X-ray diffraction pattern substantially as shown in figure 4.

According to the present invention, Differential Scanning Calorimetry (DSC) analysis of said form IV shows a first endothermic peak at a temperature close to the peak temperature of 76.2 ℃ heating, a second endothermic peak at a temperature close to the peak temperature of 115.2 ℃ heating, a first exothermic peak at a temperature close to the peak temperature of 156.2 ℃ heating, and a third endothermic peak at a temperature close to the peak temperature of 176.2 ℃.

Preferably, the thermogravimetric analysis (TGA) of form IV has a weight loss of about 3.3% upon heating to 112 ℃.

Preferably, the form IV has a DSC-TGA profile substantially as shown in figure 5.

Preferably, the form IV has a scanning electron micrograph substantially as shown in figure 6.

Preferably, the purity of said form IV may be 95% or more, preferably 98% or more, for example 99.1% or 99.5%.

the invention also provides a crystal form V of the compound 1 hemihydrate, which has characteristic peaks at 6.76 +/-0.20 °, 10.20 +/-0.20 °, 10.79 +/-0.20 °, 17.14 +/-0.20 °, 19.26 +/-0.20 °, 19.69 +/-0.20 °, 20.33 +/-0.20 °, 20.83 +/-0.20 °, 22.60 +/-0.20 °, 23.47 +/-0.20 ° and 24.73 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.

preferably, the crystal form V uses Cu-Kalpha radiation, and has the characteristic that the X-ray powder diffraction represented by the angle 2 theta has the peak values of +/-20, 31, 20, 35, 11, 31, 20, 31, 20, 27, 31, 20, 3, 14, 20, 3, 20, 26, 20, 27, 63, 20, 28, 32, 30, 75, 32, 20, 32, 81, 20, 34, 20, 31, 20, 3, 20, 3, 20, 34, 20.

preferably, the crystalline form V is obtained by using Cu-K α radiation, and X-ray powder diffraction peaks expressed in terms of 2 θ are shown in table 3, with a tolerance range ± 0.20 °:

table 3 XRPD analysis data for compound 1 form V

Preferably, the crystalline form V has a powder X-ray diffraction pattern substantially as shown in figure 7.

According to the invention, the Differential Scanning Calorimetry (DSC) analysis of said crystalline form V shows a first endothermic peak at a heating to a peak temperature of about 94.6 ℃ and a second endothermic peak at a heating to a peak temperature of about 169.0 ℃.

According to the present invention, the thermogravimetric analysis (TGA) of form V has a weight loss of about 1.8% when heated to 127 ℃.

Preferably, the crystalline form V has a DSC-TGA profile substantially as shown in figure 8.

Preferably, the purity of said form V may be 95% or more, preferably 98% or more, for example 99.1% or 99.4%.

the invention also provides a crystal form VI of the 1, 4-dioxane solvate of the compound 1, wherein the crystal form VI has characteristic peaks at 7.82 +/-0.20 degrees, 17.55 +/-0.20 degrees, 19.89 +/-0.20 degrees and 25.48 +/-0.20 degrees by X-ray powder diffraction represented by an angle of 2 theta by using Cu-Kalpha radiation.

preferably, the crystal form VI has characteristic peaks at 5.57 +/-0.20 °, 7.82 +/-0.20 °, 12.30 +/-0.20 °, 17.55 +/-0.20 °, 18.34 +/-0.20 °, 19.15 +/-0.20 °, 19.89 +/-0.20 °, 24.46 +/-0.20 ° and 25.48 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.

preferably, the crystal form VI uses Cu-Kalpha radiation, and the X-ray powder diffraction expressed by the angle of 2 theta has the characteristic 20 + -20.20 + -20 degrees, 20 + -20.20 degrees, 20 + -20 degrees, 20 + -20.20 degrees, 20 + -20 degrees, 22.03 + -0.20 degrees, 22.70 + -0.20 degrees, 23.48 + -0.20 degrees, 24.46 + -0.20 degrees, 24.71 + -0.20 degrees, 25.48 + -0.20 degrees, 26.32 + -0.20 degrees, 27.65 + -0.20 degrees, 27.98 + -0.20 degrees, 20 + -20 degrees, 20 + -20.20 + -20 degrees, 20 + -20 degrees, 20 + -20.20 + -20 degrees, 20 + -20 degrees, 20.20 degrees, 20 + -20 degrees, 20 + -20.20 degrees, 20 + -20 degrees, 20.

preferably, the crystalline form VI is obtained by using Cu-K α radiation, and X-ray powder diffraction peaks expressed in terms of 2 θ are shown in table 4, with a tolerance range ± 0.20 °:

table 4 XRPD analysis data for compound 1 form VI

Preferably, said crystalline form VI has a powder X-ray diffraction pattern substantially as shown in figure 9.

According to the invention, the Differential Scanning Calorimetry (DSC) analysis of said crystalline form VI shows a first endothermic peak at a heating to peak temperature of about 105.2 ℃ and a second endothermic peak at a heating to peak temperature of about 152.1 ℃.

According to the present invention, the thermogravimetric analysis (TGA) of said crystalline form VI has a weight loss of about 6.5% when heated to 130 ℃.

Preferably, the crystalline form VI has a DSC-TGA profile substantially as shown in figure 10.

Preferably, said form VI has a scanning electron micrograph substantially as shown in figure 11.

Preferably, the purity of said form VI may be 95% or more, preferably 99% or more, e.g. 99.5% or 99.7%.

the invention also provides an anhydrate form VII of compound 1 having characteristic peaks at 4.94 ± 0.20 °, 7.21 ± 0.20 °, 7.65 ± 0.20 °, 9.85 ± 0.20 °, 20.05 ± 0.20 °, 23.95 ± 0.20 ° by X-ray powder diffraction at 2 Θ angles using Cu-ka radiation.

preferably, the crystal form VII has characteristic peaks at 4.94 +/-0.20 degrees, 7.21 +/-0.20 degrees, 7.65 +/-0.20 degrees, 8.01 +/-0.20 degrees, 9.85 +/-0.20 degrees, 14.54 +/-0.20 degrees, 20.05 +/-0.20 degrees and 23.95 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.

preferably, the crystal form VII has characteristic peaks at 4.94 +/-0.20 °, 7.21 +/-0.20 °, 7.65 +/-0.20 °, 8.01 +/-0.20 °, 9.85 +/-0.20 °, 14.54 +/-0.20 °, 16.21 +/-0.20 °, 17.64 +/-0.20 °, 18.28 +/-0.20 °, 18.65 +/-0.20 °, 20.05 +/-0.20 °, 22.59 +/-0.20 ° and 23.95 +/-0.20 ° in X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.

preferably, the crystalline form VII is obtained by using Cu-K α radiation, and X-ray powder diffraction peaks expressed in terms of 2 θ are shown in table 5 with a tolerance range ± 0.20 °:

table 5 XRPD analysis data for compound 1 form VII

Preferably, the crystalline form VII has a powder X-ray diffraction pattern substantially as shown in figure 12.

According to the invention, the Differential Scanning Calorimetry (DSC) analysis of said crystalline form VII shows a first endothermic peak at a heating to peak temperature of around 112.1 ℃, a first exothermic peak at a heating to peak temperature of 151.7 ℃ and a second endothermic peak at a heating to peak temperature of around 176.1 ℃.

According to the present invention, the thermogravimetric analysis (TGA) of said crystalline form VII has a weight loss of about 0.9% upon heating to 95 ℃.

Preferably, the crystalline form VII of compound 1 has a DSC-TGA profile substantially as shown in figure 13.

Preferably, said crystalline form VII of compound 1 has a scanning electron micrograph substantially as shown in figure 14.

Preferably, the purity of said form VII may be 98% or more, preferably 99% or more, e.g. 99.3% or 99.6%.

The invention also provides a preparation method of the polymorphic substance.

According to the invention, a preparation method of the crystal form II is provided, which comprises the following steps:

mixing the compound 1 with a halogenated alkane solvent and water, heating and refluxing to be clear, cooling, and collecting the obtained crystal form II;

alternatively, the invention also provides a preparation method of the crystal form II, which comprises the following steps:

dissolving the compound 1 in a haloalkane solvent to obtain a clear solution, adding water, and volatilizing or evaporating the solvent to obtain the crystal form II.

The halogenated alkane solvent can be selected from one or more of dichloromethane, trichloromethane and carbon tetrachloride, and is preferably dichloromethane;

according to the invention, the ratio of the mass (g) of the compound 1 to the volume (mL) of the haloalkane solvent may be 1:2 to 50, preferably 1:5 to 20, for example 1:5 to 10;

according to the invention, the volume ratio of the haloalkane solvent to water may be 1:1 to 40:1, preferably 10:1 to 30:1, for example 20:1 to 30: 1; as illustrative examples, a volume ratio of 20:1 dichloromethane to water, or 26.7:1 dichloromethane to water;

according to the invention, the volatilization may be carried out at a temperature at which the appropriate solvent volatilizes or evaporates, for example 10-100 ℃, for example 20-60 ℃, such as 25-40 ℃.

The invention also provides a preparation method of the crystal form IV, which comprises the following steps:

dissolving the compound 1 in an ether solvent or a nitrile solvent, adding the obtained solution into water, and stirring to obtain a crystal form IV;

wherein, the ether solvent can be selected from one or more of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, 1, 4-dioxane and tetrahydrofuran, such as tetrahydrofuran;

the nitrile solvent may be selected from acetonitrile;

according to the invention, the ratio of the mass (g) of the compound 1 to the volume (mL) of the ether solvent or nitrile solvent may be 1:2 to 50, preferably 1:5 to 20, for example 1:5 to 10;

the volume ratio of the ether or nitrile solvent to water is preferably 2:1 to 4:1, such as 4:1, and as an illustrative example, tetrahydrofuran to water in a volume ratio of 2.5:1 or acetonitrile to water in a volume ratio of 4:1 is used;

the water is preferably purified water;

the stirring may be carried out at a temperature of from 0 to 40 deg.C, for example from 15 to 35 deg.C, such as from 20 to 25 deg.C.

The invention also provides a preparation method of the crystal form V, which comprises the following steps:

dissolving the compound 1 in a mixed solvent of ethers and alkane solvents to obtain a suspension, and stirring for crystallization to obtain a crystal form V;

wherein the ether solvent has the above-mentioned definition, preferably 1, 4-dioxane;

the alkane solvent may be C_6-10A linear or branched alkane, preferably n-heptane;

in the mixed solvent of the ether and the alkane solvent, the volume ratio of the ether solvent to the alkane solvent is preferably 1:1 to 1:4, for example 1:3 to 1: 4; for example, a mixed solvent of 1, 4-dioxane and n-heptane in a volume ratio of 1:4 or 1:3 is used;

according to the invention, the ratio of the mass (g) of the compound 1 to the volume (mL) of the mixed solvent may be 1:5 to 100, preferably 1:5 to 30, for example 1:5 to 10;

the stirring may be carried out at a temperature of from 0 to 40 deg.C, for example from 15 to 35 deg.C, such as from 20 to 25 deg.C.

The invention also provides a preparation method of the compound 1 crystal form VI, which comprises the following steps:

dissolving the compound 1 in a 1, 4-dioxane solvent to obtain a clear solution, adding (such as dropwise adding) an alkane solvent into the clear solution under the stirring condition, and stirring to obtain a crystal form VI;

wherein the alkane solvent has the definition as described above, preferably n-heptane;

according to the invention, the ratio of the mass (g) of the compound 1 to the volume (mL) of 1, 4-dioxane may be 1:2 to 50, preferably 1:5 to 20, for example 1:5 to 10;

the volume ratio of the 1, 4-dioxane to the alkane solvent is preferably 1:4 to 1:8, for example a mixture of 1, 4-dioxane and n-heptane in a volume ratio of 1:4, 1:5, 1:6, 1:7 or 1:8 is used.

The stirring may be carried out at a temperature of from 0 to 60 deg.C, for example from 15 to 55 deg.C, such as from 25 to 50 deg.C.

The invention further provides a preparation method of the crystal form VII, which comprises the following steps:

heating form IV of compound 1 as described above and then cooling to give form VII;

preferably, the temperature of the heating may be 80 ℃ or higher, for example, 100 to 150 ℃;

the heating time can be 5-50 min; as illustrative examples, heating and holding at 105 ℃ for 30min, or heating and holding at 120 ℃ for 20 min;

the heating is preferably carried out under an inert atmosphere, for example under a nitrogen atmosphere;

the temperature of the cooling may be 0-30 ℃.

The invention also provides a preservation method of the crystal form II, wherein the crystal form II is placed in an environment below 60 ℃, such as 0-40 ℃;

preferably, the preservation method according to form II is such that the relative humidity may be below 92.5% RH, preferably below 80% RH, for example below 60% RH.

The invention also provides a method for preserving the form IV, wherein the form IV is placed in an environment having a relative humidity of 92.5% RH or less, for example 0-80% RH.

Preferably, the preservation method according to form IV is carried out at a temperature below 60 ℃, for example between 0 and 40 ℃.

The present invention also provides a pharmaceutical composition comprising one or more of form II, form IV, form V, form VI, or form VII of compound 1, and optionally a pharmaceutically acceptable excipient.

The invention also provides a formulation comprising one or more of form II, form IV, form V, form VI, or form VII of compound 1, and optionally a pharmaceutically acceptable excipient.

The invention also provides application of one or more of the crystal form II, the crystal form IV, the crystal form V, the crystal form VI or the crystal form VII of the compound 1 in the preparation of medicines for treating and/or preventing hepatitis B virus infection.

The present invention also provides the use of a mixture of one or more of form II, form IV, form V, form VI or form VII of compound 1 as described above for the treatment and/or prevention of hepatitis b virus infection.

Definition and description of terms

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

The polymorphic substance of the compound 1 of the invention has an X-ray powder diffraction characteristic peak expressed by a 2 theta angle, wherein +/-0.20 DEG is an allowable measurement error range.

The polymorph of compound 1 of the present invention can be used in combination with other active ingredients as long as it does not produce other adverse effects, such as allergic reactions.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Polymorphs of compound 1 of the present invention can be prepared into suitable pharmaceutical compositions using known pharmaceutical carriers by those skilled in the art. The pharmaceutical compositions may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.

The pharmaceutical composition can be formulated into various dosage forms for convenient administration, for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are ready to use upon addition of a pharmaceutical vehicle prior to injection).

As used herein, the term "therapeutically and/or prophylactically effective amount" is the amount of a drug or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other person.

When used for the above-mentioned therapeutic and/or prophylactic uses, the total daily amount of the polymorphic form of compound 1 and the pharmaceutical composition of the present invention will be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved.

The invention has the beneficial effects that:

1) the polycrystalline type prepared by the invention has good stability, and the purity, color and character of the polycrystalline type are not changed after the polycrystalline type is stored for a long time at normal temperature, for example, after the polycrystalline type is stored for 180 days. The crystal form has good fluidity, is easy to crush and is easy to be used for preparing a pharmaceutical composition. Finally, the polycrystalline type prepared by the invention has high purity and less single impurity.

2) The polycrystalline type prepared by the invention has good stability and can be stored under the condition of high temperature or high humidity. For example, form II can be stored at high temperature, e.g., 60 ℃, for 10 days with no change in its form; the crystal form IV is stored in an environment with the relative humidity as high as 92.5 percent RH, and the purity, the color and the properties of the crystal form IV are not changed. The polymorphic form disclosed by the invention has excellent stability.

3) The preparation method of the polycrystalline type has the advantages of simple process, easy implementation, mild reaction conditions and high product yield. In addition, multiple purification is not needed, the operation is safe and environment-friendly, and the industrial production of the polycrystalline is facilitated.

Drawings

Figure 1 is an X-ray powder diffraction pattern of compound 1, crystalline form II.

Figure 2 is a differential scanning calorimetry thermogram and thermogravimetric analysis (DSC-TGA) of form II of compound 1.

Fig. 3 is a scanning electron micrograph of compound 1, form II.

Figure 4 is an X-ray powder diffraction pattern of compound 1 form IV.

Figure 5 is a differential scanning calorimetry thermogram and thermogravimetric analysis of form IV of compound 1.

Figure 6 is a scanning electron micrograph of compound 1, form IV.

Figure 7 is an X-ray powder diffraction pattern of compound 1 form V.

Figure 8 is a differential scanning calorimetry thermogram and thermogravimetric analysis of form V of compound 1.

Figure 9 is an X-ray powder diffraction pattern of compound 1 form VI.

Figure 10 is a differential scanning calorimetry thermogram and thermogravimetric analysis of form VI of compound 1.

Figure 11 is a scanning electron micrograph of compound 1 form VI.

Figure 12 is an X-ray powder diffraction pattern of compound 1 form VII.

Figure 13 is a differential scanning calorimetry thermogram and thermogravimetric analysis of form VII of compound 1.

Figure 14 is a scanning electron micrograph of compound 1, crystalline form VII.

Detailed Description

The polymorph of the present invention, methods of preparation and uses thereof are described in further detail below with reference to specific examples. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

A detection instrument:

(1) nuclear magnetic resonance apparatus

The instrument model is as follows: varian INOVA-400 NMR spectrometer.

And (3) testing conditions are as follows: solvent DMSO-d₆。

(2) X-ray powder diffractometer:

the instrument model is as follows: PANALYtic X-ray powder diffractometer model X' Pert PRO MPD.

And (3) testing conditions are as follows: the target material was copper, the light pipe was set to (40Kv 40mA), the diffraction mode was reflective, the scanning mode was continuous, the divergence slit was 1/4 °, and the scanning speed was 8 °/min.

(3) TGA/DSC1 synchronous thermal analyzer

The instrument model is as follows: TGA/DSC 1STAR^eSystem

And (3) testing conditions are as follows: the temperature rise rate was 10 ℃/min and dry nitrogen was used as the purge gas.

(4) Scanning Electron Microscope (SEM)

The instrument model is as follows: ZEISS Sigma 300.

(5) High performance liquid chromatograph

The instrument model is as follows: waters e 2695-2489.

Example 1 preparation of compound 1:

the reaction route is as follows:

the method comprises the following specific steps:

A50L reactor was charged with 12L of methylene chloride. Starting material (5.00kg,15.46mol) was added. 4-N, N-dimethylaminopyridine (2.83kg,23.20mol) was added and stirred for 10 minutes. Compound 2(2.23kg,15.46mol) was added and the temperature was reduced to 0 ℃. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (4.45kg,23.20mol) was dissolved in portions in dichloromethane (20L) to form a suspension. Slowly dripping, and controlling the temperature of the feed liquid to be lower than 0 ℃ in the dripping process. After the addition was complete, stirring was continued for 16 hours. Sampling and detecting, and TLC (PE: EtOAc 1: 1). After the reaction was completed, the reaction solution was washed with a saturated solution of sodium hydrogencarbonate (20L × 2). The column was washed with a saturated solution of NaCl (15L) 1 time. Concentrated under reduced pressure, spin-dried, and then 3L of toluene was added. Continuing to concentrate under reduced pressure to obtain a compound 3. The separation weight was 6.95kg, the separation yield was 87.7%, and the purity was 85%.

In a 50L reactor, anhydrous toluene (20L) was added. Compound 3(6.95kg,15.46mol) was added. While stirring, dry methanol (6.26L,154.6mol) was added. The internal temperature was controlled at 70 ℃ and stirred for 16 h. Sampling and detecting. TLC (PE: EtOAc ═ 1:1), after completion of the reaction, the reaction was concentrated under reduced pressure to give a red brown viscous liquid. The crude product was dissolved in 6L EtOH, 10L petroleum ether. The solution was stirred at 13 ℃ for 30 minutes, and a white solid precipitated. Stirring for 2 hours, standing overnight, filtering, washing the solid with petroleum ether (5L) three times, and air drying to obtain compound 4 (4.2kg,11.07mol), yield: 71.5 percent and 98 percent of purity.

Compound 4(1140g,3mol), anhydrous THF (7.5L) was added to a 30L reaction flask and stirred. Compound 5(566g,3.45mol), compound 6(502g,1.1mol) and N-methylmorpholine (760g,7.5mol) were added. The reaction was refluxed (60 ℃ C.) for 20 hours, cooled to 5-10 ℃ C, and isobutyl chloroformate (492g,3.6mol, dissolved in 500mL THF) was added dropwise and reacted at 5-10 ℃ C. for 1 hour. After the intermediate carboxylic acid is completely reacted. The reaction was quenched by the addition of water (3L). Ethyl acetate (9L) was added for extraction and the organic phase was washed 1 time with water (3L). The organic solvent was concentrated to give 2.2kg of mother liquor. The mother liquor was dissolved in ethyl acetate (3L), tetrahydrofuran (500mL) was added, n-heptane (about 9L) was slowly added dropwise, and the mixture was stirred overnight at 15 ℃ to precipitate a solid. The solid was recrystallized from tetrahydrofuran/ethyl acetate/n-heptane solvent system (5mL/5mL/10mL/g) to yield 500g of compound 8A, 96% purity, > 96% ee, 27.1% yield.

200mL of water was added to a 10L reaction flask, sodium borohydride (39.2g,1.03mol) was added and dissolved, the temperature was reduced to 0 ℃ and the tetrahydrofuran solution of the compound 8A (4.0L of tetrahydrofuran was added to the compound 8A (270.0g,0.52mol) and dissolved in water) was slowly dropped into the aqueous solution of sodium borohydride and the temperature was controlled at 0-5 ℃ for 3 hours. Sampling and detecting, and finishing the reaction. To the reaction mixture was added 750mL of hydrochloric acid (1mol/L), and the pH was adjusted to 7. The reaction solution was concentrated to give a crude product, to which 200mL of water was added. Extraction was performed with ethyl acetate (500mL x 3) and the organic phases were combined. Na for organic phase₂SO₄Drying, filtering out the drying agent, and concentrating to obtain 299g of compound 9 sample with purity of 97.23% and yield of 96.0%.

Compound 9(269.0g,0.51mol) was charged into a 5L reaction flask, and dissolved in 1.2L of methylene chloride. 4-N, N-dimethylaminopyridine (187.4g,1.53mol) was then added thereto, and the temperature was lowered to 0 ℃ with stirring. A solution of methanesulfonyl chloride (118.09g,1.03mol) in dichloromethane (50mL) was added dropwise, and after the addition was completed, the temperature was raised to 30-35 ℃ and the reaction was stirred. After the reaction is finished, adjusting the pH value to 2-3 by using 1mol/L dilute hydrochloric acid. 500mL of water was added to the reaction mixture, extracted with dichloromethane (700 mL. times.3), the organic phases were combined and the organic phase was washed with 1M NaHCO₃(300 mL. multidot.2) washing with anhydrous Na₂SO₄And (5) drying. Suction filtration is carried out, and the filtrate is concentrated to obtain 270g of the compound 10 with the yield of 85.7 percent and the purity of 88.56 percent.

To a 30L reactor were added compound 10(1.1kg, 2.1mol), 9.9kg ethyl acetate and 0.87kg concentrated hydrochloric acid. Stirring for 3 hours, after the reaction is finished, adding 4.4kg of water, separating and extracting, washing the water phase twice by using 6.82kg of dichloromethane, separating, adding 13.25kg of dichloromethane and 1.19L of methanol into the water phase, stirring, adjusting the pH value to 12-13 by using 3mol/L sodium hydroxide solution, separating, collecting an organic phase, and concentrating under pressure until the organic phase is dry to obtain 110.85 kg of compound.

Compound 11(0.082kg,0.189mol, wt 94.19%), 1, 4-dioxane (820m L), sulfamide (0.189kg,0.235mol), nitrogen substitution were sequentially added to a 30L reactor. The reaction was carried out at reflux for 2 hours. After the reaction is completed, the reaction solution is concentrated to be dry, 500mL of dichloromethane is added, the mixture is washed by purified water, dried by anhydrous sodium sulfate, the drying agent is filtered out, the filtrate is concentrated under reduced pressure, and the compound 1 with the purity of 97.8 percent is obtained by preparative chromatography separation.

¹H NMR(400MHz,DMSO-d₆)ppm 3.07(dd,J＝17.69,6.90Hz,1H)3.48(dd,J＝17.82,7.53Hz,1H)3.55(s,3H)4.10(m,J＝6.88Hz,1H)4.20(dd,J＝11.29,6.27Hz,1H)4.51(dd,J＝11.29,6.78Hz,1H)5.91(s,1H)6.76(s,2H)7.17(d,J＝7.28Hz,1H)7.22-7.29(m,2H)7.89(d,J＝3.26Hz,1H)7.98(d,J＝3.26Hz,1H)；LCMS:m/z:488.1[M+H⁺]。

Example 2 preparation of compound 1 form II:

adding 10g of the compound 1 into 100mL of dichloromethane, adding 5mL of water, stirring, heating to reflux, cooling to 0-10 ℃ after the solid is completely dissolved and clear, separating out the solid, and collecting the obtained solid, namely the target crystal form. The XRPD pattern is shown in figure 1 by X-ray powder diffraction detection; the DSC-TGA spectrum is shown in figure 2 by DSC-TGA analysis; when the sample is observed under a scanning electron microscope, the crystal morphology is shown in figure 3, and the purity is 99.6%.

Example 3 preparation of compound 1 form II:

adding 10g of the compound 1 into 200mL of dichloromethane, stirring to completely dissolve the solid, adding 7.5mL of water, continuing stirring to gradually volatilize the solvent, separating out the solid, and filtering the suspension to obtain a crystal form, wherein an XRPD pattern of the crystal form is shown in figure 1, and the purity of the crystal form is 99.3%.

Example 4 preparation of compound 1 form IV:

about 2.3g of compound 1 was added to 10mL of tetrahydrofuran, and the sample was completely dissolved with shaking. The tetrahydrofuran solution was added to 4.0mL of water in one portion and stirred for two hours. The solid obtained by centrifugal separation is detected by X-ray powder diffraction, the XRPD pattern is shown in figure 4, and the DSC-TGA pattern is shown in figure 5 by DSC-TGA analysis; when the sample is observed under a scanning electron microscope, the crystal morphology is shown in figure 6, and the purity is 99.1%.

Example 5 preparation of compound 1 form IV:

about 2.0g of compound 1 sample was added to 10mL of acetonitrile and the sample was completely dissolved by shaking. The acetonitrile solution was added to 2.5mL of water in one portion and stirred for two hours. The crystal form is obtained by centrifugal separation, the XRPD pattern of the crystal form is shown in figure 4, and the purity is 99.5%.

Example 6 preparation of compound 1 form V:

1.0g of Compound 1 was added to 10mL of a mixed solvent of 1, 4-dioxane/n-heptane (1: 4; v/v), and the resulting suspension was magnetically stirred at room temperature for 1 day and then centrifuged to obtain a solid. The XRPD pattern is shown in figure 7 by X-ray powder diffraction, and the DSC-TGA pattern is shown in figure 8 by DSC-TGA analysis, and the purity is 99.1%.

Example 7 preparation of compound 1 form V:

about 1.0g of Compound 1 was added to 8mL of a mixed solvent of 1, 4-dioxane/n-heptane (1: 3; v/v), and the resulting suspension was magnetically stirred at room temperature for 1 day and then centrifuged to obtain a solid having an XRPD pattern as shown in FIG. 7 and a purity of 99.4%.

Example 8 preparation of compound 1 form VI:

about 1.3g of Compound 1 was added to 5mL of 1, 4-dioxane to give a clear solution. To the clear solution, 30mL of n-heptane was added dropwise with shaking, and the mixture was magnetically stirred for 3 hours and then centrifuged to obtain a solid. The XRPD pattern is shown in figure 9 through X-ray powder diffraction detection, the DSC-TGA pattern is shown in figure 10 through DSC-TGA analysis, and the crystal appearance is shown in figure 11 and the purity is 99.7 percent when the sample is observed under a scanning electron microscope.

Example 9 preparation of compound 1 form VI:

adding about 2.5g of compound 1 into 12.5mL of 1, 4-dioxane, stirring to obtain a clear solution, dropwise adding 100mL of n-heptane while stirring, placing the obtained suspension solution at 50 ℃, magnetically stirring overnight, and collecting solids to obtain a crystal form, wherein an XRPD pattern of the crystal form is shown in figure 9, and the purity of the crystal form is 99.5%.

Example 10 preparation of compound 1 form VII:

a 1.2g sample of compound 1 form IV was heated to 105 ℃ under nitrogen and held at this temperature for 30 minutes and then cooled to room temperature to give a solid. The XRPD pattern is shown in figure 12 through X-ray powder diffraction detection, the DSC-TGA pattern is shown in figure 13 through DSC-TGA analysis, and the crystal appearance is shown in figure 14 and the purity is 99.6 percent when the sample is observed under a scanning electron microscope.

Example 11 preparation of compound 1 form VII:

a 1.5g sample of compound 1 form IV was heated to 120 ℃ under nitrogen and held at this temperature for 20 minutes and then cooled to room temperature to give solid form VII as a solid. The crystal form is prepared, the XRPD pattern of the crystal form is shown in figure 12, and the purity of the crystal form is 99.3%.

Example 12 Room temperature stability test

The crystal form II prepared in example 2, the crystal form IV prepared in example 4, the crystal form VI prepared in example 8 and the crystal form VII prepared in example 10 are respectively placed in a medical low-density polyethylene bag, sealed, placed at room temperature for 180 days, then respectively measured by an XRPD (X-ray diffraction) instrument by a PANalytical X-ray powder diffractometer, and the purity is detected by a high performance liquid chromatograph, so that the purity and the crystal form of the crystal forms II, IV, VI and VII after 180 days are unchanged, and the stability is excellent. The results obtained are shown in Table 6.

TABLE 6 results of room temperature stability experiments

After 180 days	Crystal form	Purity of
			Crystal form II	Without change	99.5％
Crystal form IV	Without change	99.3％
			Crystal form VI	Without change	99.7％
Crystal form VII	Without change	99.5％

Example 13 high temperature stability experiment

The stability test of the crystalline form II prepared in example 2 was performed at 60 c, and the results are shown in table 7 below.

TABLE 7 high temperature stability test results

From the results in table 7, it is clear that the stability of form II is good, and both purity and form are unchanged after 10 days of high temperature examination.

Example 14 high humidity stability test

Form IV prepared in example 4 was subjected to stability testing at 92.5% RH and the results are shown in table 8 below.

TABLE 8 high humidity stability test results

From the results in table 8, it is clear that form IV is stable, and that both purity and form are unchanged after 10 days of high temperature examination.

The embodiments of the present invention have been described above by way of example. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. Crystalline form II of compound 1 hemihydrate:

wherein the crystal form II has characteristic peaks at 4.15 +/-0.20 degrees, 4.99 +/-0.20 degrees, 8.78 +/-0.20 degrees, 9.44 +/-0.20 degrees, 18.47 +/-0.20 degrees and 18.93 +/-0.20 degrees by X-ray powder diffraction represented by a 2 theta angle by using Cu-Kalpha radiation;

preferably, the crystal form II has characteristic peaks at 4.15 +/-0.20 degrees, 4.99 +/-0.20 degrees, 7.33 +/-0.20 degrees, 8.78 +/-0.20 degrees, 9.44 +/-0.20 degrees, 10.00 +/-0.20 degrees, 18.47 +/-0.20 degrees and 18.93 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-K α radiation;

preferably, the crystal form II has the characteristic that the X-ray powder diffraction represented by the angle 2 theta has the peak at the angles of 4.15 +/-0.20 degrees, 4.99 +/-0.20 degrees, 7.33 +/-0.20 degrees, 7.88 +/-0.20 degrees, 8.78 +/-0.20 degrees, 9.44 +/-0.20 degrees, 10.01 +/-0.20 degrees, 10.96 +/-0.20 degrees, 11.61 +/-0.20 degrees, 12.54 +/-0.20 degrees, 14.18 +/-0.20 degrees, 16.65 +/-0.20 degrees, 17.49 +/-0.20 degrees, 18.47 +/-0.20 degrees, 18.93 +/-0.20 degrees, 19.62 +/-0.20 degrees, 20.13 +/-0.20 degrees, 21.49 +/-0.20 degrees, 22.08 +/-0.20 degrees, 22.51 +/-0.20 degrees, 23.59 +/-0.20 degrees, 24.68 +/-0.20 degrees, 25.37 +/-0.20 degrees, 26.56 +/-0.24.20 degrees, 27.24 +/-0.20 degrees, 27.20 degrees, 20 degrees, 28 +/-0.20 degrees, 20 degrees, 28 degrees;

preferably, the crystalline form II has a powder X-ray diffraction pattern substantially as shown in figure 1.

2. Form IV of compound 1 monohydrate:

wherein the crystal form IV has characteristic peaks at 5.04 +/-0.20 degrees, 7.20 +/-0.20 degrees, 7.68 +/-0.20 degrees, 9.81 +/-0.20 degrees, 10.08 +/-0.20 degrees and 14.43 +/-0.20 degrees by X-ray powder diffraction represented by a 2 theta angle by using Cu-Kalpha radiation;

preferably, the crystal form IV has characteristic peaks at 5.04 +/-0.20 degrees, 7.20 +/-0.20 degrees, 7.68 +/-0.20 degrees, 9.35 +/-0.20 degrees, 9.81 +/-0.20 degrees, 10.08 +/-0.20 degrees, 14.43 +/-0.20 degrees and 18.07 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-K α radiation;

preferably, the crystal form IV uses Cu-K α radiation, and the X-ray powder diffraction represented by the angle 2 theta has the characteristic that the peak of the.

3. Crystalline form V of compound 1 hemihydrate:

wherein the crystal form V uses Cu-Kalpha radiation, and has characteristic peaks at 6.76 +/-0.20 degrees, 10.20 +/-0.20 degrees, 10.79 +/-0.20 degrees, 17.14 +/-0.20 degrees, 19.26 +/-0.20 degrees, 19.69 +/-0.20 degrees, 20.33 +/-0.20 degrees, 20.83 +/-0.20 degrees, 22.60 +/-0.20 degrees, 23.47 +/-0.20 degrees and 24.73 +/-0.20 degrees in X-ray powder diffraction represented by 2 theta angles;

preferably, the crystal form V uses Cu-Kalpha radiation, and has the characteristic that the X-ray powder diffraction represented by the angle 2 theta has the peak ± 20 degrees, 20 ± 0.20 degrees, 20.33 ± 0.20 degrees, 20.83 ± 0.20 degrees, 27.63 ± 0.20 degrees, 21.71 ± 0.20 degrees, 22.29 ± 0.20 degrees, 22.60 ± 0.20 degrees, 23.47 ± 0.20 degrees, 24.73 ± 0.20 degrees, 26.32 ± 0.20 degrees, 27.63 ± 0.20 degrees, 28.32 ± 0.20 degrees, 30.75 ± 0.20 degrees, 32.81 ± 0.20 degrees, 34.20 degrees, 20 ± 0.20 degrees, 20 degrees, 34.20 ± 0.20 degrees, 34.20 degrees;

preferably, the crystalline form V has a powder X-ray diffraction pattern substantially as shown in figure 7.

4. Crystalline form VI of the 1, 4-dioxane solvate of compound 1:

wherein, the crystal form VI uses Cu-K α, and has characteristic peaks at 7.82 +/-0.20 degrees, 17.55 +/-0.20 degrees, 19.89 +/-0.20 degrees and 25.48 +/-0.20 degrees in X-ray powder diffraction represented by 2 theta angles;

preferably, the crystal form VI has characteristic peaks at 5.57 +/-0.20 °, 7.82 +/-0.20 °, 12.30 +/-0.20 °, 17.55 +/-0.20 °, 18.34 +/-0.20 °, 19.15 +/-0.20 °, 19.89 +/-0.20 °, 24.46 +/-0.20 ° and 25.48 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation;

preferably, the crystal form VI uses Cu-K α, and the X-ray powder diffraction expressed by the angle of 2 theta has the 20 + -20.20 degrees, 20 + -20 degrees, 20 + -20.20 + -20 degrees, 20 + -20.20 degrees, 20 + -20 degrees, 22.03 + -0.20 degrees, 22.70 + -0.20 degrees, 23.48 + -0.20 degrees, 24.46 + -0.20 degrees, 24.71 + -0.20 degrees, 25.48 + -0.20 degrees, 26.32 + -0.20 degrees, 27.65 + -0.20 degrees, 27.98 + -0.20 degrees, 20 + -20 degrees, 20 + -20.20 + -20 degrees, 20 + -20 degrees, 20 + -20.20 + -20 degrees, 20 + -20 degrees, 20.20 + -20 degrees, 20 + -20 degrees, 20.20 degrees, 20 + -20 degrees, 20.20 degrees, 20 + -20.20 degrees, 20 degrees, 20.;

preferably, said crystalline form VI has a powder X-ray diffraction pattern substantially as shown in figure 9.

5. Anhydrous crystalline form VII of Compound 1:

wherein the crystal form VII has characteristic peaks at 4.94 +/-0.20 degrees, 7.21 +/-0.20 degrees, 7.65 +/-0.20 degrees, 9.85 +/-0.20 degrees, 20.05 +/-0.20 degrees and 23.95 +/-0.20 degrees by X-ray powder diffraction represented by an angle of 2 theta by using Cu-Kalpha radiation;

preferably, the crystal form VII has characteristic peaks at 4.94 +/-0.20 °, 7.21 +/-0.20 °, 7.65 +/-0.20 °, 8.01 +/-0.20 °, 9.85 +/-0.20 °, 14.54 +/-0.20 °, 20.05 +/-0.20 ° and 23.95 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation;

preferably, the crystal form VII has characteristic peaks at 4.94 +/-0.20 °, 7.21 +/-0.20 °, 7.65 +/-0.20 °, 8.01 +/-0.20 °, 9.85 +/-0.20 °, 14.54 +/-0.20 °, 16.21 +/-0.20 °, 17.64 +/-0.20 °, 18.28 +/-0.20 °, 18.65 +/-0.20 °, 20.05 +/-0.20 °, 22.59 +/-0.20 ° and 23.95 +/-0.20 ° in X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.

6. A process for preparing form II according to claim 1, comprising the steps of:

mixing the compound 1 with a halogenated alkane solvent and water, heating and refluxing to be clear, cooling, and collecting the obtained crystal form II;

alternatively, the preparation method of the crystal form II may further include the following steps:

dissolving the compound 1 in a halogenated alkane solvent to obtain a clear solution, adding water, and volatilizing or evaporating the solvent to obtain a crystal form II;

the halogenated alkane solvent can be selected from one or more of dichloromethane, trichloromethane and carbon tetrachloride, and is preferably dichloromethane;

preferably, the ratio of the mass (g) of the compound 1 to the volume (mL) of the haloalkane solvent is 1:2 to 50, preferably 1:5 to 20, for example 1:5 to 10;

preferably, the volume ratio of the haloalkane solvent to water may be 1:1 to 40:1, preferably 10:1 to 30:1, for example 20:1 to 30: 1; for example, a volume ratio of 20:1 dichloromethane to water, or 26.7:1 dichloromethane to water;

preferably, the volatilization is carried out at a temperature at which the appropriate solvent volatilizes or evaporates, for example 10-100 ℃, for example 20-60 ℃, such as 25-40 ℃.

7. A process for preparing form IV according to claim 2, comprising the steps of:

dissolving the compound 1 in an ether solvent or a nitrile solvent, adding the obtained solution into water, and stirring to obtain a crystal form IV;

wherein, the ether solvent can be selected from one or more of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, 1, 4-dioxane and tetrahydrofuran, such as tetrahydrofuran;

the nitrile solvent may be selected from acetonitrile;

preferably, the ratio of the mass (g) of the compound 1 to the volume (mL) of the ether solvent or the nitrile solvent is 1:2 to 50, preferably 1:5 to 20, for example, 1:5 to 10;

the volume ratio of ether or nitrile solvent to water is preferably from 2:1 to 4:1, for example using tetrahydrofuran to water in a volume ratio of 2.5:1 or acetonitrile to water in a volume ratio of 4: 1;

the water is preferably purified water;

the stirring may be carried out at a temperature of from 0 to 40 deg.C, for example from 15 to 35 deg.C, such as from 20 to 25 deg.C.

8. A process for preparing form V according to claim 3, comprising the steps of:

dissolving the compound 1 in a mixed solvent of ethers and alkane solvents to obtain a suspension, and stirring for crystallization to obtain a crystal form V;

wherein the ether solvent may be selected from one or more of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, 1, 4-dioxane, tetrahydrofuran, such as 1, 4-dioxane;

the alkane solvent may be C_6-10A linear or branched alkane, preferably n-heptane;

in the mixed solvent of the ether and the alkane solvent, the volume ratio of the ether solvent to the alkane solvent is preferably 1:1 to 1:4, for example 1:3 to 1: 4; for example, a mixed solvent of 1, 4-dioxane and n-heptane in a volume ratio of 1:4 or 1:3 is used;

preferably, the ratio of the mass (g) of the compound 1 to the volume (mL) of the mixed solvent may be 1:5 to 100, preferably 1:5 to 30, for example 1:5 to 10;

the stirring may be carried out at a temperature of from 0 to 40 deg.C, for example from 15 to 35 deg.C, such as from 20 to 25 deg.C.

9. A process for preparing form VI according to claim 4, comprising the steps of:

dissolving the compound 1 in a 1, 4-dioxane solvent to obtain a clear solution, adding (such as dropwise adding) an alkane solvent into the clear solution under the stirring condition, and stirring to obtain a crystal form VI;

wherein the alkane solvent may be C_6-10A linear or branched alkane, preferably n-heptane;

according to the invention, the ratio of the mass (g) of the compound 1 to the volume (mL) of 1, 4-dioxane can be 1: 2-50, preferably 1: 5-20, more preferably 1: 5-10;

the volume ratio of the 1, 4-dioxane to the alkane solvent is preferably 1:4 to 1:8, for example a mixture of 1, 4-dioxane and n-heptane in a volume ratio of 1:4, 1:5, 1:6, 1:7 or 1:8 is used;

the stirring may be carried out at 0-60 deg.C, for example 15-55 deg.C, 25-50 deg.C.

10. A process for the preparation of form VII as claimed in claim 5, comprising the steps of:

heating form IV according to claim 2 followed by cooling to provide form VII;

preferably, the temperature of the heating may be 80 ℃ or higher, for example, 100 to 150 ℃;

the heating time is 5-50 min;

for example, heating and holding at 105 ℃ for 30min, or heating and holding at 120 ℃ for 20 min;

the heating is preferably carried out under an inert atmosphere, for example under a nitrogen atmosphere;

the temperature of the cooling may be 0-30 ℃.